The association between comorbidities and stigma among breast cancer survivors

This study aimed to explore the association between types and numbers of comorbidities and stigma among breast cancer survivors (BCSs). A cross-sectional study was conducted among 937 BCSs in Shanghai Cancer Rehabilitation Club. All participants were asked to fill in an online questionnaire including Stigma Scale for Chronic Illnesses 8-item version (SSCI-8) and questions on sociodemographic characteristics and health status. Multivariate linear regression was used to analyze the association between comorbidities and stigma, adjusting for confounding factors. Results showed that nearly 70% of the participants had one or more comorbidities. The participants with stroke, digestive diseases or musculoskeletal diseases had significantly higher stigma than those without the above comorbidities. In addition, stigma was higher among survivors in the group with a greater number of comorbidities. Thus, it is important to strengthen the management of stigma in BCSs, especially for those with comorbidities.

www.nature.com/scientificreports/ one of the main health problems of these patients [24][25][26] . Studies have shown that breast cancer combined with comorbidity is associated with poorer health-related QOL 27 . For BCSs, the management of coexisting chronic diseases and their attendant burdens is also an important issue in long-term survival 28 .
Stigma is also present in other diseases such as Acquired Immune Deficiency Syndrome (AIDS), mental illness, cancers, stroke, multiple sclerosis and epilepsy 4,[6][7][8][29][30][31] . A study showed that the overall level of internalized stigma of patients with anxiety disorders (n = 109) was positively associated with a comorbid personality disorder 32 , and the explanation may relate to the finding that individuals with comorbid personality disorder often experienced more severe symptoms of anxiety and depression and thus elevated the level of internalized stigma 32,33 . Another study found that felt stigma of individuals with HIV (n = 201) was associated with poor overall health, comorbid depression, anxiety and alcohol dependence 34 . Besides, a study showed that perceived alcohol stigma was significantly higher in those with internalizing comorbidity as compared to those with no comorbidity or externalizing comorbidity 35 . As yet, few studies have examined whether breast cancer combined with comorbidity is associated with more severe stigma.
This study aimed to investigate associations between comorbidities and stigma among BCSs. We hypothesized that: (1) BCSs with a particular type of comorbidity had an increased stigma; (2) the stigma was higher among BCSs with more comorbidities. Clarifying these associations may be helpful to identify priority BCS populations that may be at high risk for stigma, and it has practical implications for providing ideas for stigma intervention practices in Chinese BCS populations.

Methods
Setting and participants. In this cross-sectional study, all the participants were recruited from registered members of Shanghai Cancer Rehabilitation Club (SCRC) using a convenience sampling method 36 . SCRC is a non-government organization that has a three-level management network of the city, district, and street 37 . It recruits members from communities and hospitals through extensive recruitment channels covering all sixteen districts of Shanghai 36 . Each street or town has a WeChat group that includes all the members of that street who have registered in SCRC 36 . There is a total of about 50,000 BCSs in Shanghai, and about 5,000 registered BCSs in SCRC 37 . Before the participants were recruited, we estimated the sample size required, using the sample size formula N = ( for the cross-sectional study. In an Iranian study of 233 female breast cancer survivors recruited at three cancer centers, the SSCI-8 scale was used to assess the level of stigma of the participants 38

Comorbidities.
Participants were asked to answer either "yes" or "no" on a list of physician-diagnosed chronic diseases including diabetes mellitus, heart and cardiovascular diseases, stroke, respiratory diseases (e.g., asthma, chronic bronchitis, and chronic obstructive pulmonary disease), digestive diseases (e.g., fatty liver, chronic hepatitis, peptic ulcer, gallbladder polyp, gallstone, and hemorrhoids), and musculoskeletal diseases (e.g., osteoarthritis and rheumatoid arthritis) 40 . These chronic diseases must be clinically diagnosed by secondary or tertiary hospitals in China.
Stigma. Stigma was measured using the Stigma Scale for Chronic Illnesses 8-item version (SSCI-8), which evaluates stigmatization as a psychosocial concept referring to any act, thought, attitude, or perception toward a person with chronic conditions 36,41 . SSCI-8 is an 8-item newly developed short-form instrument, which is appropriate for patients with chronic illnesses 36 . The items are scored based on a five-point Likert scale from "never" to "always"; patients respond to items based on their personal experiences, whether they are subjected to any enacted stigma or felt stigma internally 36 . In this study, average score of the scale (ranging from 1 to 5 points) was used to evaluate stigma of the participants. The higher the score, the higher the level of stigma. The SSCI-8 has been proved to have good reliability and validity in a variety of chronic diseases 36,41,42 . However, it has not yet been used in the Chinese breast cancer population 36 . Therefore, after obtaining permission to translate and use the questionnaire, the research team translated the questionnaire, following these steps: (1)  www.nature.com/scientificreports/ eventually invited to check the translated and back-translated versions to select the most appropriate translation for each item or provided alternate translations to fit the Chinese context if the provided translations were unacceptable. (4) The Chinese version was considered final when there were no substantial differences 36,39 . A final quality review by the project members has performed again after the cognitive debriefing step was conducted, and the translation was finalized 36,39 . In this study, the Cronbach's alpha and the structural validity coefficient of SSCI-8 were 0.900 and 0.909 respectively.

Statistical analysis.
Means and standard deviations were calculated for continuous variables (age, BMI, time since diagnosis), and numbers and percentages were computed for categorical variables (marital status, education level, household per capital income, surgery, radiotherapy, chemotherapy, endocrine drug therapy, hysterectomy, recurrence, metastasis). The differences in the distribution of stigma in different demographic characteristics were also analyzed using Kruskal-Wallis H test for multi-categorical variables and Mann Whitney U test for dichotomous variables. These variables were also included as confounders in later regression analyses for the association between types or numbers of comorbidities and stigma. In order to compare the level of stigma among BCSs in different age groups, different BMI and different time of diagnosis, we transformed age, BMI and time of diagnosis into classification variables (age: < 50, 50-59, 60-69, ≥ 70 years; BMI: < 18.5 kg/m 2 , 18.5-24.9 kg/m 2 , 25.0-29.9 kg/m 2 , ≥ 30 kg/m 2 ; time of diagnosis: < 3 years, 3-5 years, 5-10 years, ≥ 10 years) during Kruskal-Wallis H test. However, they were still included as continuous variables in multiple linear regression models. The choice of sampling strategy probably had an effect on the non-normal distribution of the outcome variable. The data in the study did not conform to assumptions of normality and/or homoscedasticity/homogeneity of variance 36 . Research has shown that parametric tests (e.g., multiple regression, ANOVA) can be robust to modest violations of these assumptions 43 . Referring to the methods provided by other studies to address non-normality 44,45 , we performed data transformation-the stigma variable was inverted transformed. After transformation, each regression model included in this study met the assumption of normality and homoscedasticity/homogeneity of variances. Each regression model included one comorbidity or the number of comorbidities and the above-mentioned confounding variables. The multi-categorical variables (education level, household per capital income) were converted into dummy variables before being included in the regression models.
The multi-categorical variable number of comorbidities was also converted to a dummy variable before being included in the regression model. All statistical analyses were performed by SPSS version 20.0. A two-sided p value less than 0.05 was considered as the significant level.
The study was carried out in accordance with relevant guidelines and regulations and approved by the Medical Research Ethics Committee of the School of Public Health, Fudan University (The international registry no. IRB00002408 and FWA00002399). Informed consent was obtained from each participant prior to the start of the survey.

Results
Basic demographic characteristics and treatment. Table 1 presents participant characteristics. The average age of participants in this study was 60.55 years (SD = 6.98). BCSs in this study were mainly aged 50 and above (92.4%), and 58.5% of the survivors were over 60 years old. Most BCSs were educated in high school (45.1%) and below high school (38.4%). 86.1% of them have been married. The survival duration of most BCSs (from the first diagnosis to the survey) was no less than 5 years (79.5%). Almost all participants had surgery (99.6%) or chemotherapy (89.1%); 42.9% and 66.9% had radiotherapy and endocrine drugs respectively; 12.3% had hysterectomy. The recurrence and metastasis rates were 5.3% and 5.7% respectively. Besides, the mean survival duration for participants in this study was 10.10 years (SD = 6.45). Table 1 also shows the distribution of stigma in different demographic characteristics and treatments. Survivors with metastasis (average score of stigma was 1.79) had higher stigma scores than those without metastasis (average score of stigma was 1.61), and the difference was statistically significant (p = 0.024). No statistically significant differences in stigma were found among other demographic characteristics or treatment. Figure 1 presents the number and percentage of comorbidities among BCSs.

Comorbidities and stigma.
In this study, six types of chronic diseases were investigated: diabetes mellitus (11.3%), heart and cardiovascular diseases (11.7%), stroke (5.2%), respiratory diseases (9.9%), digestive diseases (53.1%), and musculoskeletal diseases (21.9%), were found among the participants. 67.8% of the participants had at least one comorbidity, of which 12.1% of the participants had three or more comorbidities. The average stigma score of all the participants was 1.62 points (SD = 0.59 points). The results from the multiple linear regression models are presented in Table 2. Models 3, 5, 6, and 7 were statistically significant and explained 3.1%, 3.0%, 3.1% and 3.6% of stigma among the participants, respectively. After controlling for sociodemographic factors and other health conditions, participants with stroke, digestive diseases, or musculoskeletal diseases had significantly higher stigma scores than those without these disorders. Compared with participants without comorbidities, participants with 1-2 chronic diseases and participants with 3 or more comorbidities had significantly higher stigma scores.

Discussion
This study evaluated the association between comorbidities and stigma in BSCs. The results showed that, after controlling for confounding factors, participants with stroke, digestive diseases or musculoskeletal diseases had significantly higher stigma scores than those without these diseases. Also, participants with more comorbidities had higher stigma scores.
In this study, there were no statistically significant associations between social demographic factors and stigma among the breast cancer survivors, which differs from previous studies, showing that stigma is influenced  46 . Although our study did not find meaningful correlations, it showed similar tendencies on some variables. Therefore, these demographic characteristics remained factors that couldn't be ignored in the study of stigma and should be given attention. We controlled for these factors as confounders when exploring the association between comorbidities and stigma. In addition to sociodemographic factors, treatment modalities were also found to be unrelated to stigma among BCSs. However, participants who received surgery, radiotherapy, chemotherapy or endocrine drugs showed a tendency to have higher levels of stigma. Breast cancer treatment leads to physical disability and physical changes 5,10 , which damage the self-esteem of patients and cause strong feelings of shame as they perceive themselves as losing their femininity 47,48 . However, some studies claimed that the stigma was not related to the specific treatment and that patients felt the same stigma whether they underwent mastectomy or breastconserving treatment 49 . In this study, participants with metastasis had a significantly higher level of stigma. For  Table 2. Associations between comorbid chronic diseases and stigma in BCSs. SE, standard error. *p < 0.05; **p < 0.01. In all these models, the dependent variable stigma was inverted transformed. And the following confounding factors were considered in each model: age, BMI and time since diagnosis as continuous variables, marital status, surgery, radiotherapy, chemotherapy, endocrine drug therapy, hysterectomy, recurrence and metastasis as dichotomous variables, education level and household per capital income as multi-categorical variables were converted into dummy variables before being included in the regression models. In model 7, the independent variable number of comorbidities was also converted into dummy variable (set dummy variables c1, c2; when number of comorbidities = 0, c1 = 0 and c2 = 0; when number of comorbidities = 1-2, c1 = 1 and c2 = 0; when number of comorbidities ≥ 3, c1 = 0 and c2 = 1). In all these models, all the variation inflation factor (VIF) values were below 10. www.nature.com/scientificreports/ BCSs with metastases, the disease is more severe and the treatment may be more complicated, which makes them extremely psychologically stressed and more likely to perceive discrimination. Therefore, they are more prone to be victims of stigma 20 . In this study, several common chronic diseases, such as stroke, digestive diseases and musculoskeletal diseases, were related to the stigma of BCSs. These common chronic diseases exacerbate physical or financial burdens, which may enhance the overall perceived stigma of BCSs and further increase internalized stigma. Stroke patients usually have a limitation of activities caused by physical impairment, and are at increased risk of emotional processing disorders due to reduced social interaction and participation, resulting in increased stigma 30,50 . Stigma is also an important health issue in gastrointestinal diseases, which is related to the negative impression of society on such diseases and the serious psychological burden of patients. Patients with such diseases often feel embarrassed and reluctant to seek treatment and nursing, which brings more serious health problems 51 . Musculoskeletal diseases bring about reduced physical activity, weakness, decreased well-being and loss of independence, and seriously limit the ability of patients to change their lifestyle, thereby affecting the social network of patients and bringing stigma 52,53 .
The average score of stigma in this study was 1.62 points (± 0.59 points), which was higher than that in Iran (1.47 points ± 0.19 points) 38 . The difference may be related to the different cultural backgrounds, perceptions and acceptance of the disease in different countries. Rooted in the values of interdependence, Chinese culture emphasizes the importance of maintaining one's face and social status 54 . Previous studies have shown that some traditional Chinese beliefs include the idea that disease is the result of bad karma, or the punishment for prior misdeeds conducted by the individuals or their ancestors [55][56][57] . Therefore, the diagnosis of breast cancer or chronic diseases has the potential to undermine a person's perceived social status, which may lead to shame and selfblame, bringing with it a severe sense of stigma 58 . Stigma has been reported in AIDS patients 59 . The coexistence of disease, poverty and drug abuse will increase stigma 59 . Among BCSs, the economic burden caused by disease treatment, nursing and loss of work, the serious decline of physical function and the dependence on daily nursing may facilitate thoughts of uselessness. Survivors may define themselves as the burden of the whole family, and produce negative self-perception of themselves, which is the source of stigma 9 . Moreover, patients with both cancer and comorbidities may have a more severe decline in physical function, require more nursing and care, and therefore may have a greater degree of stigma. In this study, breast cancer and comorbidities can also lead to an overlay of stigma. And the higher the number of comorbidities, the more severe the stigma. Therefore, the issue of stigma in BCSs with comorbidities needs attention.
R-squared values in this study were small to some extent. Usually in the prediction model, the larger the R-squared value, the better the regression model fits the observations 60 . Fortunately, despite the low R-squared value, if the independent variables are statistically significant, important conclusions can still be drawn about the relationships between the variables 60 . In this study, regression models were used to explore the association between types and numbers of comorbidities and stigma among BCSs. Stigma is a very complex variable related to multiple factors in individual-related, disease-related, social contact, and support network dimensions 61,62 . However, due to various constraints, the independent variables included in this study were limited and the explanation of stigma was also limited. Nevertheless, the association between the types and numbers of comorbidities and stigma among BCSs is undeniable. Thus, this study calls for attention to the population of BCSs with comorbidities in psychological interventions such as stigma.
There are some limitations in this study. Firstly, respondents could have responded in a positive manner. Thus, stigma was not a guaranteed presence for all respondents and there was no way of determining the experience of stigma for each respondent prior to administering the questionnaires. Secondly, the sample might not be representative of an entire population, therefore findings were limited to this sample of respondents. Thirdly, the study collected online questionnaires through WeChat, a Chinese social networking platform. This survey method could lead to bias in content understanding as the investigator and participants couldn't communicate face-toface. However, in the context of COVID-19 pandemic, such online investigation had its unique advantages in terms of organization and implementation 36 . Besides, online surveys faced the risk of poor questionnaire quality, as participants could respond without reading the questions or submit questionnaires repeatedly 36,39 . To avoid these situations, we made some settings at the technical level, including limiting people using the same device or the same WeChat account to fill out the questionnaire only once and setting multiple logic test questions 36,39 . Finally, this study was a cross-sectional study, which had the disadvantage of insufficient demonstration of causality among research variables. Further research is still needed to clarify the causal associations of the association among similarly variables or factors.

Conclusions
In conclusion, the study indicated that the stigma of BCSs with certain chronic diseases (stroke, digestive diseases or musculoskeletal diseases) was significantly higher than that of those who are not suffering from these diseases, and the stigma of BCSs was higher among those with more comorbidities. BCSs with comorbidities may be a priority population at risk for stigma and need more attention in the future long-term care and psychological interventions for community BCSs.

Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.